In German patent application P 39 21 059.6, 11.beta.-aryl-4-estrenes of general formula I ##STR11## are described for the first time, in which
X stands for an oxygen atom, the hydroxy imino grouping &gt;N OH or two hydrogen atoms,
R.sup.1 stands for a hydrogen atom or a methyl group,
R.sup.2 stands for a hydroxy group, a C.sub.1 -C.sub.10 alkoxy or C.sub.1 -C.sub.10 acyloxy group,
R.sup.3 stands for a hydrogen atom, the grouping --(CH.sub.2).sub.n CH.sub.2 Z, in which n is 0, 1, 2, 3, 4 or 5, Z means a hydrogen atom, the cyano group or the radical --OR.sup.5 with R.dbd..sup.5 H, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 acyl, the grouping --(CH.sub.2).sub.m --C.tbd.C--Y, in which m means 0, 1 or 2 and Y means a hydrogen, fluorine, chlorine, bromine or iodine atom, a C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 alkoxyalkyl, C.sub.1 -C.sub.10 acyloxyalkyl radical, the grouping --CH.dbd.CH--(CH.sub.2).sub.k CH.sub.2 R.sup.6, in which k means 0, 1 or 2 and R.sup.6 means a hydrogen atom, a hydroxy group, a C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 acyloxy radical, or else R.sup.2 and R.sup.3 together stand for a radical of formula ##STR12##
R.sup.4 stands for a hydrogen atom, for a straight-chain or branched, saturated or unsaturated C.sub.1 -C.sub.8 alkyl, acyl or alkoxyalkyl radical, for an amino group ##STR13## in which R.sup.7 and R.sup.8, independent of one another, mean a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, or for a corresponding amine oxide ##STR14## or for the grouping --OR.sup.9, in which R.sup.9 means a hydrogen atom, a methyl, ethyl, propyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group, or for a heteroaryl radical of formula I.alpha. ##STR15## in which A symbolizes a nitrogen, oxygen or sulfur atom, -B-D-E-symbolizes the element sequence --C--C--C--, --N--C--C-- or --C--N--C-- and R.sup.10 symbolizes a hydrogen atom, a cyano, trialkylsilyl, trialkylstannyl or amino group ##STR16## or the radical --OR.sup.9 or --SR.sup.9 with R.sup.7, R.sup.8 and R.sup.9 in the already indicated meaning, or for a heteroaryl radical of formula I.beta. ##STR17## in which A means a nitrogen atom and -B-D-E- means the element sequence of --C--C--C--, --N--C--C--, --C--N--C-- or --C--C--N-- and R.sup.10 has the already indicated meaning, or for a phenyl radical of formula I.gamma. ##STR18## in which R.sup.10 has the already indicated meaning, as well as their pharmacologically compatible addition salts with acids.
The new compounds are of great interest first of all because of their strong antigestagen properties. They are produced according to German patent application P 39 21 059.6:
Treatment of compounds of general formula II ##STR19## in which
R.sup.1 and R.sup.4 have the meaning indicated in formula I,
A stands for a .beta.-hydroxy group or the radical R.sup.2 and
B stands for an .alpha.-hydrogen atom, an .alpha.-position radical R.sup.3 or
A and B together stand for a keto-oxygen atom, with acid in an inert solvent with heating results in compounds of general formula Ia ##STR20## in which R.sup.1, A and B have the meaning indicated in formula II and R4' has the same meaning as R.sup.4 in formula I, provided that R.sup.4 is stable under the above-mentioned drastic reaction conditions.
Preferably for isomerization it is heated to a temperature between 80.degree. and 120.degree. C., namely in an inert solvent such as toluene.
The reaction time is at least 45 minutes, but can, if necessary, be 24 hours or more.
As acids, both mineral and organic acids are suitable; of the latter, p-toluenesulfonic acid is preferred.
In the compounds of general formula Ia, an end compound of general formula I can be involved if substituents R.sup.4, A and B in the initial compound of general formula II are those substituents which withstand the drastic reaction conditions necessary for isomerization. In particular, free hydroxy groups on a tertiary carbon atom are eliminated under these reaction conditions.
But it can always be useful to introduce, only after the isomerization, substituents R.sup.2 and R.sup.3 on the C-17 atom or to synthesize R.sup.4 in the 4-position of the 11.beta.-phenyl radical.
Depending on substituents R.sup.2, R.sup.3 and R.sup.4 finally desired in the compound of general formula I, after the isomerization, optionally either
a) in the compound of general formula Ia, if A in it stands for a .beta.-hydroxy group and B stands for an .alpha.-hydrogen atom, optionally the 17-hydroxy group is oxidized to a 17-keto group and
b) the 3-keto function is converted to a dithioketal, and also all other optionally present keto groups are ketalized or else first b) and then a) is performed and then
c) in case R.sup.4' in the 3-thioketalized compound stands for a methoxy or a hydroxy group and R.sup.4 in the finally desired compound of general formula I is not to stand for a methoxy or hydroxy group, the hydroxy compound, optionally after cleavage of the methoxy compound, is converted to a corresponding perfluoroalkylsulfonic acid compound, in which -alkyl- stands for a C.sub.1 -C.sub.4 alkyl radical, and from the latter either directly by reaction with a correspondingly substituted tin(trialkyl) compound R.sup.4" --Sn(alkyl).sub.3, in which R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomeric precursor of R.sup.4 and -alkyl- means a C.sub.1 -C.sub.4 alkyl radical or indirectly by a compound substituted in 4-position of the 11.beta.-phenyl radical with a tin(trialkyl) radical (alkyl.dbd.C.sub.1 -C.sub.4), which was obtained by reaction of the perfluoroalkylsulfonate compound with Sn.sub.2 alkyl.sub.6, and further treatment of the 11.beta.-(4-trialkylstannyl)-phenyl compound with a compound R.sup.4" --Y, in which R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomeric precursor of R.sup.4 and Y means a leaving group, preferably a halogen atom and especially a bromine atom, in the presence of a transition metal catalyst, a compound of general formula III is produced ##STR21## in which Z means a keto group prospected in the form of a dithioketal, and
d) then, if R.sup.2 and R.sup.3 in the finally desired compound of general formula I are not to stand for a hydroxy group or a hydrogen atom or else R.sup.2 and R.sup.3 together are not to stand for a keto-oxygen atom, desired substituents R.sup.2 and R.sup.3 are introduced on a C-17 atom of the steroid skeleton according to methods known in the art or else first d) and then c) is performed, protecting groups are cleaved, optionally free hydroxy groups are alkylated or acylated and optionally with hydroxylamine hydrochloride, the 3-keto group is converted to a 3-hydroxyimino grouping &gt;N.about.OH or the 3-keto group is converted to the dihydro compound as well as optionally a pharmaceutically compatible addition salt is produced with an acid.
The performance of process steps a), b), c) and d) takes place according to methods known in the art.
Oxidation a) of the hydroxy to keto group can be performed, for example, according to Oppenauer or with chromic acid reagents (Jones reagent) or chromic acid-pyridine.
As a protecting group for the 3-keto function, preferably the ethane-1,2-diyl-bis(thio) group is used, which can be introduced on the steroid-3-C atom by reaction of the 3-keto compound with ethane-1,2-dithiol in the presence of, e.g., p-toluenesulfonic acid.
To protect the keto group of the acyl group possible in R.sup.4, the ethylenedioxy or 2,2-dimethylpropylene-1,3-dioxy group is suitable. Also, other standard protecting groups are possible.
Alternatively, first the oxidation and then the protecting group introduction or else first the protecting group introduction and then the oxidation can be performed.
Reaction step c) is used for the synthesis of substituents R.sup.4 or R.sup.4' in p-position on the 11.beta.-phenyl ring. This process is then necessary if R.sup.4 represents a substituent which does not withstand the drastic isomerization conditions, for example, an allyl or vinyl radical.
The 11.beta.-(4-hydroxyphenyl) compound, which is obtainable from the corresponding methoxy compound by ether cleavage, for example, with sodium methanethiolate in a solvent such as dimethylformamide, is used as a starting point for this synthesis.
By reaction of the hydroxy compound with a perfluoro-(C.sub.1 -C.sub.4)-alkylsulfonic acid anhydride or halide in the presence of a base such as pyridine or 4-(dimethylamino)-pyridine, the corresponding 11.beta.-[4-(perfluoroalkylsulfonyloxy)phenyl] compound is attained (P. J. Stang, M. Hanack and L. R. Subramanian, Synthesis 85, (1982)).
In this case, the process is performed either so that in a transition metal-catalyzed reaction (preferably Pd.sup.o), the perfluoroalkylsulfonate leaving group with basically almost simultaneous substitution is displaced by the desired substituent or its precursor (J. E. McMurry and S. Mohanraj, Tetrahedron Letters, 24, No. 27, pp. 2723-2726, 1983; X. Lu and J. Zhu, Communications, pp. 726-727, 1987; Q. -Y. Chen and Z. -Y. Yang, Tetrahedron Letters 27, No. 10, pp. 1171-1174, 1986; S. Cacchi, P. G. Ciattini, F. Morera and G. Ortar, Tetrahedron Letters, 27, No. 33, pp. 3931-3934, 1986; A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc. 1987, 109, pp. 5478-5486) or a corresponding tri-organylstannyl, preferably tri-n-alkylstannyl compound is produced intermediately and transition metal-catalyzed from the perfluroroalkylsulfonate compound [J. K. Stille, Angew. Chem. [Appl. Chem.], pp. 504-519]. This is then reacted in a one-pot process with a halogen, preferably bromine- or iodine-substituted carbocyclic or heterocyclic aromatic compound [Y. Yamamoto, Y. Azuma, H. Mitoh, Communications, pp. 546-565, 1986; T. J. Bailey, Tetrahedron Letters, 27, No. 37, pp. 4407- 4410, 1986], which optionally can have still other substituents; the 11.beta.-phenyl radical then exhibits in it the desired substitution or a precursor of the desired substitution,.
Numerous such reactions with steroids, in which a trifluoromethanesulfonate group is in 4-position of an 11.beta.-phenyl ring, are described in EP-A-0283428.
Free hydroxy groups can be alkylated or acylated in a way known in the art.
Dialkylamines can be converted by suitable oxidizing agents (e.g., hydrogen peroxide or peracids) to the desired N oxides [see, e.g., Kontakte [Contacts] (Darmstadt) 1986, 3, p. 12].
Compounds with a dialkylamine substituent on the 11.beta.-phenyl ring can be converted by reaction with bromocyanogen in aprotic solvents such as, for example, dioxane, benzene or toluene at increased temperature (amine catabolism according to Braun) analogously to the instructions indicated, for example, in Org. Reactions 7, 198 (1953), K. W. Bentley, Techniques of Organic Chemistry 11, 773 (1963) and Houben-Weyl, 5/4, 151 (1960) in good yield to the corresponding (N-cyano-N-alkylaminoaryl)-derivatives.
The latter are reduced depending on the finally desired meaning of ##STR22## in the end product in a way known in the art to the corresponding dialkylamine compounds (for example, with diisobutyl aluminum hydride in toluene to the N-formyl-N-alkylaminophenyl intermediate products and then with lithium aluminum hydride) or N--H--N-alkyl compounds (for example, with lithium aluminum hydride or with lithium in liquid ammonia). The latter are then optionally acylated in a way known in the literature and optionally then reduced to the new dialkylamine derivative in a known way with, for example, lithium aluminum hydride (see DE 36 23 038).
In process step d), substituents R.sup.2 and R.sup.3 finally desired on the 17-C atom finally are introduced, unless a methoxy or hydroxy group already comprised from the start as R.sup.2 or a hydrogen atom as R.sup.3 or a keto-oxygen atom formed together from R.sup.2 and R.sup.3 is involved. This introduction takes place analogously to processes known in the literature (for example, J. Fried, J. A. Edwards, "Organic Reactions in Steroid Chemistry," Van Nostrand Reinhold Company, 1972, Vol. 1 and 2; "Terpenoids and Steroids," Specialist Periodical Report, The Chemical Society, London, Vol. 1-12) by nucleophilic addition to the C-17 ketone.
Detailed data in this connection is found in German patent application P 39 21 059.6 and in corresponding European patent application EP-A-0404283.